Phenylindole derivatives as 5-HT2A receptor ligands

ABSTRACT

A class of tryptamine analogues bearing an optionally substituted phenyl nucleus at the 2-position are selective antagonists of the human 5-HT 2A  receptor and are therefore useful as pharmaceutical agents, especially in the treatment and/or prevention of adverse neurological conditions, including psychotic disorders such as schizophrenia.

This application is a 371 of PCT/GB98/02616 filed Sep. 1, 1998.

The present invention relates to the use of a class of indolederivatives which act on serotonin receptors (also known as5-hydroxytryptamine or 5-HT receptors). More particularly, the inventionconcerns analogues of tryptamine bearing an optionally substitutedphenyl substituent at the 2-position. These compounds are selectiveantagonists of the human 5-HT_(2A) receptor and are therefore useful aspharmaceutical agents, especially in the treatment and/or prevention ofadverse conditions of the central nervous system, including psychoticdisorders such as schizophrenia.

Schizophrenia is a disorder which is conventionally treated with drugsknown as neuroleptics. In many cases, the symptoms of schizophrenia canbe treated successfully with so-called “classical” neuroleptic agentssuch as haloperidol. Classical neuroleptics generally are antagonists atdopamine D₂ receptors.

Notwithstanding their beneficial antipsychotic effects, classicalneuroleptic agents such as haloperidol are frequently responsible foreliciting acute extrapyramidal symptoms (movement disorders) andneuroendocrine (hormonal) disturbances. These side-effects, whichplainly detract from the clinical desirability of classicalneuroleptics, are believed to be attributable to D₂ receptor blockade inthe striatal region of the brain.

The compound(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol(also known as MDL-100,907) is described in WO 91/18602. In preclinicalstudies, MDL-100,907 failed to induce catalepsy and failed to blockapomorphine-induced stereotyped behaviour in animal models, stronglysuggesting that this compound would be free from any liability to causeextrapyramidal side-effects. MDL-100,907 is currently undergoingclinical trials in schizophrenic patients and has demonstrated efficacyin a multicentre, placebo-controlled study for antipsychotic potential,with no neurological adverse effects. Pharmacologically, MDL-100,907 hasbeen shown to be a potent antagonist of human 5-HT_(2A) receptors,whilst being essentially devoid of activity at the human dopamine D₂receptor. It is accordingly believed that compounds which can interactselectively with the 5-HT_(2A) receptor relative to the dopamine D₂receptor will display the beneficial level of antipsychotic activityassociated with 5-HT_(2A) receptor antagonism, whilst minimizing or evenavoiding the extrapyramidal and other side-effects arising from aninteraction with dopamine D₂ receptors.

The compounds of use in the present invention are potent antagonists ofthe human 5-HT_(2A) receptor, and are accordingly of benefit in thetreatment and/or prevention of psychotic disorders such asschizophrenia. The compounds of use in the invention may display moreeffective binding to the human 5-HT_(2A) receptor than to the humandopamine D₂ receptor, and they can therefore be expected to manifestfewer side-effects than compounds which do not discriminate in theirbinding affinity as between 5-HT_(2A) and D₂ receptors.

By virtue of their potent human 5-HT_(2A) receptor antagonist activity,the compounds of use in the present invention are also effective in thetreatment of neurological conditions including depression, anxiety,panic disorder, obsessive-compulsive disorder, pain, sleep disorderssuch as insomnia, eating disorders such as anorexia nervosa, anddependency or acute toxicity associated with narcotic agents such as LSDor MDMA; and cardiovascular conditions including variant angina,Raynaud's phenomenon, intermittent claudication, coronary and peripheralvasospasms, fibromyalgia, cardiac arrhythmias and thrombotic illness.They may also be generally of benefit in the inhibition of plateletaggregation, as well as in controlling the extrapyramidal symptomsassociated with the administration of neuroleptic agents. They mayfurther be effective in the lowering of intraocular pressure and maytherefore be beneficial in treating glaucoma (cf. T. Mano et al. and H.Takaneka et al., Investigative Ophthalmology and Visual Science, 1995,vol. 36, pages 719 and 734 respectively).

Being 5-HT_(2A) receptor antagonists, the compounds of use in thepresent invention may also be beneficial in preventing or reducing thetoxic symptoms associated with the intake of ergovaline in animalsconsuming Acremonium coenophialum infected tall fescue (cf. D. C. Dyer,Life Sciences, 1993, 53, 223-228).

The preparation of a series of indole derivatives, including3-aminoalkyl-2-phenylindoles, for pharmacological study is described inAmes et al., J. Chem. Soc., 1959, 3388-3399. No actual pharmaceuticalutility is, however, ascribed to the compounds disclosed therein.

Julia et al. in Annales de l'Institut Pasteur, 1965, 343-362, describethe preparation of a number of 2-aryltryptamine derivatives, which arestated to have weak antiserotonin (rat uterus) activity.

Agarwal et al. in Indian Drugs, 1979, 209-212, and in J. Indian Chem.Soc., 1980, 57, 742-743, describe the synthesis of inter alia thecompound 3- [2-(2-methylpiperidin-1-yl)ethyl]-2-phenyl-1H-indole.However, no pharmacological activity is ascribed in either publicationto this specific compound.

In JP-A-55-151505 is described a class of indoles, including3-aminoalkyl-2-phenylindole derivatives which are optionally substitutedon the 2-phenyl moiety and on the benzo moiety of the indole nucleus.These compounds are stated therein to be fungicides.

Hiriyakkanavar & Siddappa in Indian J. Chem., 1966, 4, 188-190, describethe synthesis of various 5,7-dimethyl-substituted 2-phenyltryptaminederivatives, which are stated to exhibit antiserotonin activity.

Joshi et al. in Agric. Biol. Chem., 1978, 42, 1723-1726, and in Monatsh.Chem., 1980:, 111, 1343-1350, describe various fluorinated analogues of2-phenyltryptamine. Certain of these compounds are stated to act as mildstimulants.

In none of the prior art publications referred to above, in which2-phenyl analogues of tryptamine are described, is there any disclosureor suggestion that such compounds might be potent and selectiveantagonists of the human 5-HT_(2A) receptor, nor indeed that they mightbe of particular benefit in the treatment in particular of neurologicalconditions, including psychotic disorders such as schizophrenia.

FR-A-2102282 and FR-A-2181559 describe separate series of inter alia2-phenyltryptamine analogues, both of which are stated to possess avariety of actions on the nervous system.

The compounds of use in the present invention are potent and selective5-HT_(2A) receptor antagonists having a human 5-HT_(2A) receptor bindingaffinity (K_(i)) of 100 nM or less, typically of 50 nM or less andpreferably of 10 nM or less. The compounds of use in the invention maypossess at least a 10-fold selective affinity, suitably at least a20-fold selective affinity and preferably at least a 50-fold selectiveaffinity, for the human 5-HT_(2A) receptor relative to the humandopamine D₂ receptor.

The present invention provides the use of a compound of formula I, or apharmaceutically acceptable salt thereof:

wherein

A and B independently represent hydrogen, halogen, cyano, nitro,trifluoromethyl, trifluoromethoxy, C₁₋₆ alkyl or C₁₋₆ alkoxy;

X and Y independently represent hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆alkoxy or phenyl;

R¹ represents hydrogen or C₁₋₆ alkyl;

R² represents hydrogen, methyl, ethyl, 2-methoxyethyl, n-propyl,isopropyl, n-butyl, 2-methylpropyl, tert-butyl or n-pentyl; and

R³ represents C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₉ cycloalkyl, aryl, C₃₋₇heterocycloalkyl, C₃₋₇ heterocycloalkyl(C₁₋₆)alkyl, heteroaryl orheteroaryl(C₁₋₆)alkyl, any of which groups may be optionally substitutedby one or more substituents; or

R² and R³ taken together with the intervening nitrogen atom represent agroup of formula (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k),(l) or (m):

in which the broken line represents an optional chemical bond;

Z represents oxygen, sulphur, N—R⁶ or CR⁷R⁸;

R⁴ represents hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy(C₁₋₆)alkyl, C₃₋₇heterocycloalkyl(C₁₋₆)alkyl or aryloxy;

R⁵ represents hydrogen, C₁₋₆ alkyl or C₁₋₆ alkoxy(C₁₋₆)alkyl;

R⁶ represents hydrogen, —COR⁹ or —CO₂R⁹; or C₁₋₆ alkyl, C₂₋₆ alkenyl,C₃₋₉ cycloalkyl, aryl(C₁₋₆)alkyl, aryl(C₂₋₆)alkenyl, C₃₋₇heterocycloalkyl(C₁₋₆)alkyl or heteroaryl, any of which groups may beoptionally substituted by one or more substituents;

R⁷ represents hydrogen, hydrocarbon, a heterocyclic group, —COR⁹ or—CO₂R⁹;

R⁸ represents hydrogen, phenyl or acetoxy; and

R⁹ represents C₁₋₆ alkyl;

for the manufacture of a medicament for the treatment and/or preventionof clinical conditions for which a selective antagonist of 5-HT_(2A)receptors is indicated, especially psychotic disorders includingschizophrenia.

The present invention also provides a method for the treatment and/orprevention of clinical conditions for which a selective antagonist of5-HT_(2A) receptors is indicated, especially psychotic disordersincluding schizophrenia, which comprises administering to a patient inneed of such treatment an effective amount of a compound of formula I asdefined above or a pharmaceutically acceptable salt thereof.

A particular subset of compounds of use in the present inventioncomprises the compounds of formula I as depicted above, andpharmaceutically acceptable salts thereof, wherein

A, B, X, Y and R¹ are as defined above;

R² represents hydrogen, methyl or ethyl; and

R³ represents C₁₋₆ alkyl, C₃₋₉ cycloalkyl, aryl, C₃₋₇ heterocycloalkyl,C₃₋₇ heterocycloalkyl(C₁₋₆)alkyl, heteroaryl or heteroaryl(C₁₋₆)alkyl,any of which groups may be optionally substituted by one or moresubstituents; or

R² and R³ taken together with the intervening nitrogen atom represent agroup of formula (a) to (k) as defined above, in which

R⁴ represents hydrogen or C₁₋₆ alkyl; and

Z, R⁵, R⁶, R⁷, R⁸ and R⁹ are as defined above.

For use in medicine, the salts of the compounds of formula I will bepharmaceutically acceptable salts. Other salts may, however, be usefulin the preparation of the compounds of use in the invention or of theirpharmaceutically acceptable salts. Suitable pharmaceutically acceptablesalts of the compounds of use in this invention include acid additionsalts which may, for example, be formed by mixing a solution of thecompound of use in the invention with a solution of a pharmaceuticallyacceptable acid such as hydrochloric acid, sulphuric acid,methanesulphonic acid, fumaric acid, maleic acid, succinic acid, aceticacid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonicacid or phosphoric acid. Furthermore, where the compounds of use in theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include alkali metal salts, e.g. sodium or potassiumsalts; alkaline earth metal salts, e.g. calcium or magnesium salts; andsalts formed with suitable organic ligands, e.g. quaternary ammoniumsalts.

The term “hydrocarbon” as used herein includes straight-chained,branched and cyclic groups containing up to 18 carbon atoms, suitably upto 15 carbon atoms, and conveniently up to 12 carbon atoms. Suitablehydrocarbon groups include C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₉cycloalkyl, C₃₋₉ cycloalkyl(C₁₋₆)alkyl, indanyl, aryl, aryl(C₁₋₆)alkyland aryl(C₂₋₆)alkenyl.

The expression “a heterocyclic group” as used herein includes cyclicgroups containing up to 18 carbon atoms and at least one heteroatompreferably selected from oxygen, nitrogen and sulphur. The heterocyclicgroup suitably contains up to 15 carbon atoms and conveniently up to 12carbon atoms, and is preferably linked through carbon. Examples ofsuitable heterocyclic groups include C₃₋₇ heterocycloalkyl, C₃₋₇heterocycloalkyl(C₁₋₆)alkyl, heteroaryl and heteroaryl(C₁₋₆)alkylgroups.

Suitable alkyl groups include straight-chained and branched alkyl groupscontaining from 1 to 6 carbon atoms. Typical examples include methyl andethyl groups, and straight-chained or branched propyl, butyl and pentylgroups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, n-pentyl and 2,2-dimethylpropyl.

Suitable alkenyl groups include straight-chained and branched alkenylgroups containing from 2 to 6 carbon atoms. Typical examples includevinyl, allyl, 2-methylpropenyl and dimethylallyl groups.

Suitable alkynyl groups include straight-chained and branched alkynylgroups containing from 2 to 2 carbon atoms. Typical examples includeethynyl and propargyl groups.

Suitable cycloalkyl groups include groups containing from 3 to 9 carbonatoms. Particular cycloalkyl groups are cyclopropyl, cyclopentyl,cyclohexyl and cyclooctyl.

Typical examples of C₃₋₉ cycloalkyl(C₁₋₆)alkyl groups includecyclopropylmethyl, cyclohexylmethyl and cyclohexylethyl.

Particular indanyl groups include indan-1-yl and indan-2-yl.

Particular aryl groups include phenyl and naphthyl.

Particular aryl(C₁₋₆)alkyl groups include benzyl, phenylethyl,phenylpropyl, phenylbutyl and naphthylmethyl.

Typical aryl(C₂₋₆)alkenyl groups include phenylethenyl andphenylpropenyl.

Suitable heterocycloalkyl groups include tetrahydrofuryl,tetrahydrothienyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyland morpholinyl groups.

Typical C₃₋₇ heterocycloalkyl(C₁₋₆)alkyl groups includetetrahydrofurylmethyl, morpholinylethyl and pyrrolidinylpropyl.

Suitable heteroaryl groups include pyridinyl, quinolinyl, isoquinolinyl,pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furyl, benzofuryl,dibenzofuryl, thienyl, benzthienyl, pyrrolyl, indolyl, pyrazolyl,indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl,benzimidazolyl, benzimidazolonyl, oxadiazolyl, thiadiazolyl, triazolyland tetrazolyl groups.

The expression “heteroaryl(C₁₋₆)alkyl” as used herein includesfurylmethyl, furylethyl, thienylmethyl, thienylethyl, oxazolylmethyl,oxazolylethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethyl,imidazolylethyl, oxadiazolylmethyl, oxadiazolylethyl,thiadiazolylmethyl, thiadiazolylethyl, triazolylmethyl, triazolylethyl,tetrazolylmethyl, tetrazolylethyl, pyridinylmethyl, pyridinylethyl,pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl andisoquinolinylmethyl.

The hydrocarbon and heterocyclic groups, as well as the substituents R³and R⁶, may in turn be optionally substituted by one or more groups,preferably by one or two optional groups, selected from C₁₋₆ alkyl,adamantyl, phenyl or halophenyl (except when R³ is C₁₋₃ alkyl), benzyl,thiadiazolyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ aminoalkyl, difluoromethyl,trifluoromethyl, hydroxy, C₁₋₆ alkoxy, difluoromethoxy,trifluoromethoxy, aryloxy, benzyloxy, OXO, C₁₋₃ alkylenedioxy,1,3-dioxabutylene, nitro, cyano, carboxy, C₂₋₆ alkoxycarbonyl, C₂₋₆alkoxycarbonyl(C₁₋₆)alkyl, C₂₋₆ alkylcarbonyloxy, arylcarbonyloxy,aminocarbonyloxy, C₂₋₆ alkylcarbonyl, arylcarbonyl, C₁₋₆ alkylthio, C₁₋₆alkylsulphinyl, C₁₋₆ alkylsulphonyl, arylsulphonyl, —NR^(v)R^(w),—NR^(v)COR^(w), —NR^(v)CO₂R^(w), —NR^(v)SO₂R^(w), —CH₂NR^(v)SO₂R^(w),—NHCONR^(v)R^(w), —CONR^(v)R^(w), —SO₂NR^(v)R^(w) and—CH₂SO₂NR^(v)R^(w), in which R^(v) and R^(w) independently representhydrogen, C₁₋₆ alkyl, aryl or aryl(C₁₋₆)alkyl, or R^(v) and R^(w)together represent a C₂₋₆ alkylene group.

When R^(v) and R^(w) together represent a C₂₋₆ alkylene group, thisgroup may be an ethylene, propylene, butylene, pentamethylene orhexamethylene group, preferably butylene or pentamethylene.

The term “halogen” as used herein includes fluorine, chlorine, bromineand iodine, especially fluorine or chlorine.

Where the compounds of use in the invention have at least one asymmetriccentre, they may accordingly exist as enantiomers. Where the compoundsof use in the invention possess two or more asymmetric centres, they mayadditionally exist as diastereoisomers. It is to be understood that theuse of all such isomers and mixtures thereof in any proportion isencompassed within the scope of the present invention.

Particular values for the substituent A in the compounds of formula Iabove include hydrogen, fluoro, trifluoromethyl and methyl, especiallyhydrogen.

Suitably, B represents hydrogen, fluoro, chloro, cyano, nitro,trifluoromethyl, trifluoromethoxy, methyl or methoxy.

Particular values for the substituent X include hydrogen and fluoro,especially hydrogen.

Suitably, Y represents hydrogen, fluoro, chloro, bromo, methyl, methoxyor phenyl.

Suitably, R¹ represents hydrogen or methyl, especially hydrogen.

Suitably, R² represents hydrogen, methyl or ethyl, typically hydrogen ormethyl.

In one embodiment, R² represents hydrogen. In another embodiment, R² ismethyl.

Illustrative values of R³ include methyl, ethyl, n-propyl, isopropyl,n-butyl, 2-methylpropyl, tert-butyl, n-pentyl, 2-methylpropenyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, phenyl,tetrahydrothienyl, piperidinyl, tetrahydrofurylmethyl, morpholinylethyl,pyrrolidinylpropyl, morpholinylpropyl and furylmethyl, any of whichgroups may be optionally substituted by one or more substituents.

Representative values of R³ include methyl, ethyl, n-propyl, isopropyl,cyclopropyl, cyclopentyl, cyclooctyl, phenyl, tetrahydrothienyl,piperidinyl, tetrahydrofurylmethyl, morpholinylethyl, pyrrolidinylpropyland furylmethyl, any of which groups may be optionally substituted byone or more substituents.

The moiety R³ may be unsubstituted, or substituted by one or moresubstituents. Preferably, R³ is unsubstituted, or substituted by one ortwo substituents. Examples of typical substituents on the moiety R³include benzyl, fluoro, chloro, bromo, trifluoromethyl, methoxy, ethoxy,isopropoxy, difluoromethoxy, trifluoromethoxy, oxo, 1,3-dioxabutyleneand diisopropylamino.

Specific values of R³ include methyl, ethyl, fluoroethyl,trifluoroethyl, methoxyethyl, diisopropylamino-ethyl, n-propyl,fluoropropyl, isopropyl, n-butyl, 2-methylpropyl, tert-butyl, n-pentyl,2-methylpropenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cyclooctyl, phenyl, fluorophenyl, chlorophenyl, dichlorophenyl,methoxyphenyl, dimethoxyphenyl, trimethoxyphenyl, ethoxyphenyl,isopropoxyphenyl, difluoromethoxy-phenyl, trifluoromethoxy-phenyl,1,3-dioxabutylenephenyl, tetrahydrothienyl dioxide, benzyl-piperidinyl,tetrahydrofurylmethyl, morpholinethyl, pyrrolidinylpropyl,morpholinylpropyl and furylmethyl.

Particular values of R³ include methyl, ethyl, diisopropylaminoethyl,n-propyl, isopropyl, cyclopropyl, cyclopentyl, cyclooctyl, phenyl,fluorophenyl, chlorophenyl, dichlorophenyl, methoxyphenyl,dimethoxyphenyl, trimethoxyphenyl, ethoxyphenyl, isopropoxyphenyl,difluoromethoxy-phenyl, trifluoromethoxy-phenyl,1,3-dioxabutylenephenyl, tetrahydrothienyl dioxide, benzyl-piperidinyl,tetrahydrofurylmethyl, morpholinylethyl, pyrrolidinylpropyl andfurylmethyl.

In one embodiment, Z represents oxygen or sulphur. In anotherembodiment, Z represents CR⁷R⁸.

In a further embodiment, Z represents oxygen, sulphur or N—R⁶. In astill further embodiment, Z represents N—R⁶ or CR⁷R⁸. In a yet furtherembodiment, Z represents oxygen, sulphur or CR⁷R⁸.

Suitably, R⁴ represents hydrogen, methyl, methoxymethyl,pyrrolidinylmethyl or phenoxy, especially hydrogen or methoxymethyl, andmore especially hydrogen. More particularly, R⁴ may represent hydrogenor methyl, especially hydrogen.

Suitably, R⁵ represents hydrogen, methyl, ethyl, n-propyl ormethoxymethyl, especially hydrogen.

Illustrative values of R⁶ include hydrogen, acetyl andtert-butoxycarbonyl; and methyl, ethyl, n-propyl, isopropyl, allyl,cyclopentyl, cyclohexyl, benzyl, phenylethyl, phenylethenyl,morpholinylethyl, pyridinyl, quinolinyl, isoquinolinyl, pyrimidinyl andbenzofuryl, any of which groups may be optionally substituted by one ormore substituents.

Representative values of R⁶ include hydrogen, acetyl andtert-butoxycarbonyl; and methyl, ethyl, propyl, allyl, cyclohexyl,benzyl, phenylethyl, phenylethenyl, morpholinylethyl, pyridinyl,quinolinyl, isoquinolinyl, pyrimidinyl and benzofuryl, any of whichgroups may be optionally substituted by one or more substituents.

The moiety R⁶ may be unsubstituted, or substituted by one or moresubstituents. Preferably, R⁶ is unsubstituted, or substituted by one ortwo substituents. Examples of typical substituents on the moiety R⁶include methyl, ethyl, tert-butyl, phenyl, fluorophenyl, chlorophenyl,fluoro, chloro, trifluoromethyl, methoxy, ethoxy, benzyloxy,methylenedioxy, nitro, cyano, acetoxy, methylthio, dimethylamino,diethylamino, dipropylamino, N-methyl-N-phenylaminocarbonyl andpyrrolidinylcarbonyl. More specific examples of typical substituents onthe moiety R⁶ include methyl, ethyl, tert-butyl, phenyl, fluorophenyl,chlorophenyl, fluoro, chloro, trifluoromethyl, methoxy, ethoxy,benzyloxy, methylenedioxy, nitro, cyano, acetoxy, methylthio,dimethylamino, diethylamino, N-methyl-N-phenylaminocarbonyl andpyrrolidinylcarbonyl.

Specific values for the moiety R⁶ include hydrogen, acetyl,tert-butoxycarbonyl, methyl, benzyloxymethyl,N-methyl-N-phenylaminocarbonyl-methyl, pyrrolidinylcarbonyl-methyl,ethyl, methoxyethyl, acetoxyethyl, dimethylamino-ethyl,diethylamino-ethyl, dipropylamino-ethyl, dimethylamino-propyl,isopropyl, allyl, cyclopentyl, cyclohexyl, benzyl, tert-butylbenzyl,diphenylmethyl, (chlorophenyl)(phenyl)methyl, di(fluorophenyl)methyl,di(chlorophenyl)methyl, chlorobenzyl, methylenedioxy-benzyl,1-phenylethyl, 2-phenylethyl, chlorophenyl-ethenyl, cyanophenyl-ethenyl,morpholinylethyl, pyridinyl, trifluoromethyl-pyridinyl,(chloro)(trifluoromethyl)pyridinyl, trifluoromethyl-quinolinyl,isoquinolinyl, pyrimidinyl, trifluoromethyl-pyridimidinyl andbenzofuryl.

Particular values of R⁶ include hydrogen, acetyl, tert-butoxycarbonyl,methyl, benzyloxymethyl, N-methyl-N-phenylaminocarbonyl-methyl,pyrrolidinylcarbonyl-methyl, ethyl, methoxyethyl, acetoxyethyl,diethylamino-ethyl, dimethylamino-propyl, allyl, cyclohexyl, benzyl,tert-butylbenzyl, diphenylmethyl, (chlorophenyl)(phenyl)methyl,di(fluorophenyl)methyl, di(chlorophenyl)methyl, chlorobenzyl,methylenedioxy-benzyl, phenylethyl, chlorophenyl-ethenyl,cyanophenyl-ethenyl, morpholinylethyl, pyridinyl,trifluoromethyl-pyridinyl, (chloro)(trifluoromethyl)pyridinyl,trifluoromethyl-quinolinyl, isoquinolinyl, pyrimidinyl,trifluoromethyl-pyridimidinyl and benzofuryl.

Suitable values of R⁷ include hydrogen, C₂₋₆ alkylcarbonyl and C₂₋₆alkoxycarbonyl; and C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₇ cycloalkyl, aryl,aryl(C₁₋₆)alkyl1, aryl(C₂₋₆)alkenyl, C₃₋₇ heterocycloalkyl(C₁₋₆)alkyland heteroaryl, any of which groups may be optionally substituted by oneor more substituents.

Representative values of R⁷ include hydrogen, acetyl andtert-butoxycarbonyl; and methyl, ethyl, propyl, allyl, cyclohexyl,phenyl, benzyl, phenylethyl, phenylpropyl, phenylbutyl, phenylethenyl,phenylpropenyl, morpholinylethyl, pyridinyl, quinolinyl, isoquinolinyl,pyrimidinyl, benzofuryl and benzimidazolonyl, any of which groups may beoptionally substituted by one or more substituents.

The moiety R⁷ may be unsubstituted, or substituted by one or moresubstituents. Preferably, R⁷ is unsubstituted, or substituted by one ortwo substituents. Examples of typical substituents on the moiety R⁷include methyl, ethyl, tert-butyl, phenyl, fluorophenyl, chlorophenyl,fluoro, chloro, trifluoromethyl, methoxy, ethoxy, benzyloxy,methylenedioxy, nitro, cyano, acetoxy, methylthio, dimethylamino,diethylamino, N-methyl-N-phenylaminocarbonyl and pyrrolidinylcarbonyl.

Specific values for the moiety R⁷ include hydrogen, acetyl,tert-butoxycarbonyl, methyl, benzyloxymethyl,N-methyl-N-phenylaminocarbonyl-methyl, pyrrolidinylcarbonyl-methyl,ethyl, methoxyethyl, acetoxyethyl, diethylamino-ethyl,dimethylamino-propyl, allyl, cyclohexyl, phenyl, methylphenyl,dimethylphenyl, ethylphenyl, fluorophenyl, chlorophenyl, dichlorophenyl,trifluoromethyl-phenyl, (chloro)(trifluoromethyl)phenyl,bis(trifluoromethyl)phenyl, methoxyphenyl, (dichloro)(methoxy)phenyl,dimethoxyphenyl, trimethoxyphenyl, ethoxyphenyl, methylenedioxy-phenyl,nitrophenyl, (dinitro)(trifluoromethyl)phenyl, cyanophenyl,dicyanophenyl, methylthiophenyl, benzyl, tert-butylbenzyl,diphenylmethyl, (chlorophenyl)(phenyl)methyl, di(fluorophenyl)methyl,di(chlorophenyl)methyl, chlorobenzyl, methylenedioxy-benzyl,phenylethyl, 3,3-diphenylpropyl, 4-phenylbut-2-yl, chlorophenyl-ethenyl,cyanophenyl-ethenyl, phenylpropenyl, morpholinylethyl, pyridinyl,trifluoromethyl-pyridinyl, (chloro)(trifluoromethyl)pyridinyl,trifluoromethyl-quinolinyl, isoquinolinyl, pyrimidinyl,trifluoromethyl-pyridimidinyl, benzofuryl and benzimidazolonyl.

In relation to formula (c) above in which Z represents CR⁷R⁸, the moietyR⁷ suitably represents hydrogen, methyl, benzyloxymethyl, phenyl,methoxyphenyl, benzyl, phenylethyl or benzimidazolonyl. Moreparticularly, R⁷ in this context may suitably represent hydrogen,benzyloxymethyl, benzyl, phenylethyl or benzimidazolonyl.

In relation to formula (e) above, the moiety R⁷ suitably representsmethylenedioxy-phenyl, chlorophenyl-ethenyl, cyanophenyl-ethenyl orbenzofuryl.

In relation to formula (f) above, the moiety R⁷ suitably representsbenzyl.

Suitably, R⁸ represents hydrogen.

Suitably, R⁹ represents methyl or tert-butyl.

Specific compounds of use in the present invention include:

3-[2-(N,N-dimethylamino)ethyl]-2-phenyl-1H-indole;

3-[2-(N,N-diethylamino)ethyl]-2-phenyl-1H-indole;

2-phenyl-3-[2-(pyrrolidin-1-yl)ethyl]-1H-indole;

2-phenyl-3-[2-(piperidin-1-yl)ethyl]-1H-indole;

3-[2-(2-methylpiperidin-1-yl)ethyl]-2-phenyl-1H-indole;

3-[2-homopiperidin-1-yl)ethyl]-2-phenyl-1H-indole;

3-[2-(morpholin-4-yl)ethyl]-2-phenyl-1H-indole ;

2-(4-fluorophenyl)-3-[2-(piperidin-1-yl)ethyl]-1H-indole;

and pharmaceutically acceptable salts thereof.

Certain compounds falling within the definition of formula I above arenovel. Accordingly, in a further aspect, the present invention providesa compound of formula I as defined above, or a salt thereof, wherein Brepresents trifluoromethyl or trifluoromethoxy.

In another aspect, the present invention provides a compound of formulaI as defined above, or a salt thereof, wherein Y represents phenyl.

In another aspect, the present invention provides a compound of formulaI as defined above, or a salt thereof, provided that:

(i) when A and B independently represent hydrogen, halogen, cyano,nitro, alkyl or alkoxy, and X and Y independently represent hydrogen,halogen, alkyl or alkoxy, then either R³ does not represent alkyl, or R²and R³ taken together with the intervening nitrogen atom do notrepresent piperidin-1-yl or morpholin-4-yl; and

(ii) when A, B, X, Y and R¹ each represents hydrogen, then R² and R³taken together with the intervening nitrogen atom do not representpyrrolidin-1-yl, 2-methylpiperidin-1-yl or homopiperidin-1-yl.

Particular sub-classes of novel compounds in accordance with the presentinvention are represented by the compounds of formula IA and IB, andsalts thereof:

wherein R² and R³ are as defined above.

Specific compounds in accordance with the present invention includethose compounds disclosed in the accompanying Examples, with theexception of Example Nos. 1, 9, 22, 34, 36, 38, 49 and 55.

The invention also provides pharmaceutical compositions comprising oneor more of the novel compounds according to the invention in associationwith a pharmaceutically acceptable carrier. Preferably thesecompositions are in unit dosage forms such as tablets, pills, capsules,powders, granules, sterile parenteral solutions or suspensions, meteredaerosol or liquid sprays, drops, ampoules, auto-injector devices orsuppositories; for oral, parenteral, intranasal, sublingual or rectaladministration, or for administration by inhalation or insufflation.Alternatively, the compositions may be presented in a form suitable foronce-weekly or once-monthly administration; for example, an insolublesalt of the active compound, such as the decanoate salt, may be adaptedto provide a depot preparation for intramuscular injection. An erodiblepolymer containing the active ingredient may be envisaged. For preparingsolid compositions such as tablets, the principal active ingredient ismixed with a pharmaceutical carrier, e.g. conventional tabletingingredients such as corn starch, lactose, sucrose, sorbitol, talc,stearic acid, magnesium stearate, dicalcium phosphate or gums, and otherpharmaceutical diluents, e.g. water, to form a solid preformulationcomposition containing a homogeneous mixture of a compound of thepresent invention, or a pharmaceutically acceptable salt thereof. Whenreferring to these preformulation compositions as homogeneous, it ismeant that the active ingredient is dispersed evenly throughout thecomposition so that the composition may be readily subdivided intoequally effective unit dosage forms such as tablets, pills and capsules.This solid preformulation composition is then subdivided into unitdosage forms of the type described above containing from 0.1 to about500 mg of the active ingredient of the present invention. Favoured unitdosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50or 100 mg, of the active ingredient. The tablets or pills of the novelcomposition can be coated or otherwise compounded to provide a dosageform affording the advantage of prolonged action. For example, thetablet or pill can comprise an inner dosage and an outer dosagecomponent, the latter being in the form of an envelope over the former.The two components can be separated by an enteric layer which serves toresist disintegration in the stomach and permits the inner component topass intact into the duodenum or to be delayed in release. A variety ofmaterials can be used for such enteric layers or coatings, suchmaterials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol andcellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

In the treatment of schizophrenia, a suitable dosage level is about 0.01to 250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, andespecially about 0.05 to 5 mg/kg per day. The compounds may beadministered on a regimen of 1 to 4 times per day.

If desired, the compounds of use in this invention may beco-administered with another anti-schizophrenic medicament, for exampleone producing its effects via dopamine D₂ and/or D₄ receptor subtypeblockade. In such circumstances, an enhanced anti-schizophrenic effectmay be envisaged without a corresponding increase in side-effects suchas those caused by, for example, D₂ receptor subtype blockade; or acomparable anti-schizophrenic effect with reduced side-effects mayalternatively be envisaged. Such co-administration may be desirablewhere a patient is already established on an anti-schizophrenictreatment regime involving conventional anti-schizophrenic medicaments.Suitable anti-schizophrenic medicaments of use in combination with thecompounds according to the present invention include haloperidol,chlorpromazine, mesoridazine, thioridazine, acetophenazine,fluphenazine, perphenazine, trifluoperazine, chloroprothixene,thiothixene, clozapine, olanzapine, pimozide, molindone, loxapine,sulpiride, risperidone, xanomeline, fananserin and ziprasidone, andpharmaceutically acceptable salts thereof.

The compounds of formula I above, including the novel compoundsaccording to the present invention, may be prepared by a process whichcomprises reacting a compound of formula II with a compound of formulaIII:

wherein A, B, X, Y, R¹, R² and R³ are as defined above, L¹ represents asuitable leaving group and R^(p) represents a hydrogen atom, anamino-protecting group or an attached resin moiety; followed, wherenecessary, by removal of the amino-protecting group or attached resinmoiety R^(p).

The leaving group L¹ is suitably an alkylsulphonyloxy orarylsulphonyloxy moiety such as trifluoromethanesulphonyloxy(triflyloxy) or p-toluenesulphonyloxy (tosyloxy), preferably triflyloxy.

Where R^(p) represents an amino-protecting group, this is suitably acarbamoyl moiety, e.g. tert-butoxycarbonyl (BOC), which can readily beremoved as required by treatment with acid, typically trifluoroaceticacid, or with base, e.g. sodium methoxide in methanol.

Where R^(p) represents an attached resin moiety, this is suitably apolymeric moiety such as the commercially available WANG resin, wherebythe substituent R^(p) represents (4-benzyloxycarbonyl)phenoxymethylcopoly(styrene-1% divinylbenzene). The WANG resin can beconveniently removed at the appropriate stage by treatment withpyrrolidine at an elevated temperature, typically in a solvent such asN,N-dimethylformamide.

The reaction between compounds II and III is conveniently effected bystirring in an appropriate solvent, e.g. dichloromethane,1,2-dichloroethane or N,N-dimethylformamide, optionally under basicconditions, for example in the presence of potassium carbonate.

In an alternative procedure, the compounds of formula I above, includingthe novel compounds according to the invention, may be prepared by aprocess which comprises reacting a compound of formula IV with acompound of formula V:

wherein A, B, X, Y, R¹, R², R³ and R^(p) are as defined above; one of M¹and M² represents a suitable leaving group, and the other represents aboronic acid moiety —B(OH)₂ or a ₁₋₄ alkyl ester or anhydride thereof;in the presence of a transition metal catalyst; followed, wherenecessary, by removal of the amino-protecting group or attached resinmoiety R^(p).

The leaving group M¹ or M² is suitably a halogen atom, e.g. bromine.

The transition metal catalyst of use in the reaction between compoundsIV and V is suitably tetrakis(triphenylphosphine)palladium (0);. Thereaction is conveniently carried out in an inert solvent such asethanolic toluene, aqueous tetrahydrofuran or aqueous1,2-dimethoxyethane, advantageously in the presence of a base such assodium acetate or sodium carbonate, optionally in the presence oflithium chloride, and typically at an elevated temperature.

Where L¹ represents triflyloxy or tosyloxy, the intermediates of formulaII above may be prepared by triflylation or tosylation of thecorresponding 3-(2-hydroxyethyl)indole derivative using standardtechniques, e.g. by treatment with triflic anhydride (Tf₂O), typicallyin a solvent such as dichloromethane or 1,2-dichloroethane andoptionally in the presence of a base such as2,6-di-tert-butyl-4-methylpyridine. The hydroxy compound may in turn beprepared by reaction of a compound of formula V as defined above with acompound of formula VI:

wherein X, Y, R¹, R^(p) and M¹ are as defined above, and R^(q)represents hydrogen or a hydroxy-protecting group; under conditionsanalogous to those defined above for the reaction between compounds IVand V; followed, where necessary, by removal of the hydroxy-protectinggroup R^(q).

Where R^(q) represents a hydroxy-protecting group, this is ideally atetrahydro-2H-pyran-2-yl moiety, which can conveniently be removed asnecessary under acidic conditions, for example by treatment withpyridinium p-toluenesulphonate (PPTS) in a suitable solvent, e.g.ethanol or a mixture of ethanol and 1,2-dichloroethane.

The intermediates of formula IV may be prepared by reacting a compoundof formula III as defined above with a compound of formula VII:

wherein X, Y, R¹, R^(p), L¹ and M¹ are as defined above; underconditions analogous to those described above for the reaction betweencompounds II and III.

Where L¹ represents triflyloxy or tosyloxy, the intermediates of formulaVII may be prepared by triflylation or tosylation of the appropriatecompound of formula VI wherein R^(q) represents hydrogen, using standardtechniques.

In another procedure, the compounds of formula I above, including thenovel compounds according to the invention, may be prepared by a processwhich comprises reacting a compound of formula III as defined above witha compound of formula VIII:

wherein A, B, X, Y, R¹ and R^(p) are as defined above; in the presenceof a reducing agent; followed, where necessary, by removal of theamino-protecting group or attached resin moiety R^(p).

A suitable reducing agent for use in the reaction between compounds IIIand VIII is sodium triacetoxyborohydride. The reaction is convenientlyeffected in the presence of acetic acid, typically in an inert solventsuch as 1,2-dichloroethane.

In a further procedure, the compounds of formula I above, including thenovel compounds according to the invention, may be prepared by a processwhich comprises reacting a compound of formula IX or an acid additionsalt thereof, typically the hydrochloride salt, with a compound offormula X:

wherein A, B, X, Y, R¹, R² and R³ are as defined above.

The reaction between compounds IX and X, which is an example of thewell-known Fischer indole synthesis, is suitably effected by stirring inethanol at 25° C., followed by heating in trifluoroacetic acid at 70° C.

In a still further procedure, the compounds of formula I above,including the novel compounds according to the invention, may beprepared by a process which comprises reacting a compound of formula XIwith a compound of formula XII (cf Larock and Yum, J. Am. Chem. Soc.,1991, 113, 6689):

wherein A, B, X, Y, R¹, R² and R³ are as defined above; in the presenceof a transition metal catalyst.

Similarly, the intermediates of formula II, or their hydroxy precursors,and the intermediates of formula VIII may be prepared by reacting acompound of formula XI as defined above with the appropriate compound offormula XIII or XIV:

wherein A, B and R¹ are as defined above, and L¹¹ corresponds to themoiety L¹ or represents hydroxy; in the presence of a transition metalcatalyst.

The transition metal catalyst employed in the reaction between compoundXI and compound XII, XIII or XIV is suitably a palladium-containingcatalyst. Typical catalysts include palladium(II) acetate, optionally inthe presence of triphenylphosphine, anddichlorobis(triphenylphosphine)palladium(II). A preferred catalyst isdichlorobis(triphenylphosphine)palladium(II).

The transition metal catalysed indole formation reaction betweencompound XI and compound XII, XIII or XIV is advantageously carried outunder basic conditions. Typical basic reagents of use in the reactioninclude sodium carbonate, potassium carbonate, sodium acetate orpotassium acetate, optionally in the presence of lithium chloride ortetra-n-butylammonium chloride; and tetramethylguanidine. A preferredbase is tetramethylguanidine. The reaction is conveniently effected in apolar aprotic organic solvent such as N,N-dimethylformamide, typicallyat an elevated temperature, e.g. a temperature in the region of 80-110°C.

Where they are not commercially available, the starting materials offormula III, V, VI, IX, X, XI, XII, XIII and XIV may be prepared byprocedures analogous to those described in the accompanying Examples, orby standard methods well known from the art.

It will be appreciated that any compound of formula I initially obtainedfrom any of the above processes may, where appropriate, subsequently beelaborated into a further desired compound of formula I using techniquesknown from the art.

Where the above-described processes for the preparation of the compoundsof use in the invention give rise to mixtures of stereoisomers, theseisomers may be separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques such aspreparative HPLC, or the formation of diastereomeric pairs by saltformation with an optically active acid, such as(−)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaricacid, followed by fractional crystallization and regeneration of thefree base. The compounds may also be resolved by formation ofdiastereomeric esters or amides, followed by chromatographic separationand removal of the chiral auxiliary.

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991. The protecting groups may be removed at a convenientsubsequent stage using methods known from the art.

The following Examples illustrate the preparation of compounds of use inthe invention.

The compounds useful in this invention potently inhibit [³H]-ketanserinbinding to the human 5-HT_(2A) receptor expressed in clonal cell lines.Moreover, those compounds of use in the invention which have been testeddisplay a selective affinity for the 5-HT_(2A) receptor relative to thedopamine D₂ receptor.

The compounds of the accompanying Examples were all found to possess aK_(i) value for displacement of [³H]-ketanserin from the human 5-HT_(2A)receptor, when expressed in Chinese hamster ovary (CHO) clonal celllines, of 100 nM or less.

EXAMPLES 1 TO 107 Method A:2-Phenyl-3-[2-(piperidin-1-yl)ethyl]-1H-indole (Example 1)

(a)1-tert-Butoxycarbonyl-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-indole

4-Dimethylaminopyridine (409 mg) was added to a stirred solution of3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-indole (T. Fukuyama, J. Am.Chem. Soc., 1994, 116, 3127; 8.22 g) and di-tert-butyl dicarbonate (7.37g) in dry DCM at room temperature. The resulting solution was stirred atroom temperature for 2 h at which time it was diluted with DCM (200 ml)and washed with citric acid (10% aq; 100 ml). The organic layer wasseparated and dried over MgSO₄, filtered and the solvent removed underreduced pressure to give a yellow oil (12.83 g); ¹H (250 MHz, CDCl₃)δ1.60-2.00 (6H, br m), 1.66 (9H, s), 2.99 (2H, t, J=7.5 Hz), 3.47 (1H,m), 3.75 (1H, m), 3.85 (1H, m), 4.00 (1H, m), 4.95 (1H, t, J=2.5 Hz),7.20 (1H, t, J=7.5 Hz), 7.33 (1H, t, J=7.5 Hz), 7.44 (1H, s), 7.57 (1H,d, J=5.0 Hz) and 8.12 (1H, br d, J=5.0 Hz).

(b)1-tert-Butoxycarbonyl-2-bromo-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-indole

tert-Butyllithium (28.1 ml of a 1.7 mol solution in pentane) was addedslowly to a stirred solution of1-tert-butoxycarbonyl-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-indole(15.0 g) in dry ether at −78° C. under a dry nitrogen atmosphere. Duringthe addition the temperature was maintained below −65° C. The reactionwas stirred at −78° C. for 45 min at which time1,2-dibromotetrafluoroethane (6.24 ml) was added. The reaction mixturewas then allowed to warm to room temperature over 18 h, after which timeit was quenched with water (100 ml) and extracted into ether (250 ml).The organic layer was separated, washed with water (250 ml) and brine(250 ml), dried over MgSO₄, filtered and the solvent removed underreduced pressure to give an orange oil. Purification by flashchromatography (SiO₂; n-hexane/ethyl acetate 10:1) afforded the productas a pale yellow oil (7.12 g); ¹H (250 MHz, CDCl₃) δ1.50-2.00 (6H, brm), 1.61 (9H, s), 3.05 (2H, t, J=7.5 Hz), 3.43 (1H, m), 3.56 (1H, m),3.74 (1H, m), 3.91 (1H, m), 4.61 (1H, t, J=2.5 Hz), 7.26 (2H, m), 7.54(1H, d, J=5.0 Hz) and 8.07 (1H, d, J=5.0 Hz).

(c) 2-Bromo-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-indole

1-tert-Butoxycarbonyl-2-bromo-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-indole(7.12 g) was added to a 1 mol solution of sodium methoxide in methanol(200 ml) and the resulting mixture warmed to 60° C. for 2 h. Aftercooling the solvent was removed under reduced pressure and the residuepurified immediately by flash chromatography (SiO₂; n-hexane/ethylacetate 10:1) to give the product as a pale yellow oil (4.79 g); 1H (250MHz, CDCl₃) δ1.60-2.00 (6H, br m), 3.03 (2H, t, J=7.5 Hz), 3.42 (1H, m),3.67 (1H, m), 3.78 (1H, m), 3.83 (1H, m), 4.63 (1H, t, J=2.5 Hz), 7.09(2H, m), 7.25 (1H, d, J=5.0 Hz), 7.58 (1H, d, J=5.0 Hz) and 8.09 (1H, brs).

(d) Coupling of2-bromo-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-indole to4-nitronphenylcarbonate WANG resin

2-Bromo-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-indole (3.50 g) andcommerically available 4-nitrophenylcarbonate WANG resin (10.80 g, 1.0mmol/g) were combined together in dry toluene (25 ml) and the solventremoved under reduced pressure. This procedure was repeated twice. Therecovered dry mixture was suspended in dry toluene (75 ml) and cooled to−78° C. under a dry nitrogen atmosphere. Potassiumbis(trimethylsilyl)-amide (21.6 ml of a 0.5 mol solution in toluene) wasthen added. The solution was allowed to stir at −78° C. for 10 min andthen allowed to warm to room temperature over 1 h. The resin was thenfiltered off and washed with DMF (4×250 ml), DCM (4×250 ml), MeOH (4×250ml) and ether (250 ml) to give1-[4-benzyloxycarbamoyl]phenoxymethyl-copoly(styrene-1%-divinylbenzene)-2-bromo-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-indole.The recovered resin was then re-suspended in dry DCM (100 ml) and cappedby treatment with excess dimethylamine (2×20 ml; 1.0 mol solution inTHF), then dried under high vacuum overnight. The resin was once againfiltered and the wash procedure repeated using DMF (4×250 ml), DCM(4×250 ml), MeOH (4×250 ml) and ether (250 ml). A portion of therecovered resin (100 mg) was then suspended in dry DMF (3.0 ml)containing 5% pyrrolidine and heated to 110° C. for 4 h. The resin wasfiltered off and the solvent removed from the filtrate under reducedpressure to afford the recovered starting material giving a loading of0.62 mmol/g; ¹H (250 MHz, CDCl₃) δ1.60-2.00 (6H, br m), 3.03 (2H, t,J=7.5 Hz), 3.42 (1H, m), 3.67 (1H, m), 3.78 (1H, m), 3.83 (1H, m), 4.63(1H, t, J=2.5 Hz), 7.09 (2H, m), 7.25 (1H, d, J=5.0 Hz), 7.58 (1H, d,J=5.0 Hz) and 8.09 (1H, br s).

(e)1-[4-Benzyloxycarbamoyl]phenoxymethyl-copoly(styrene-1%-divinylbenzene)-2-phenyl-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-indole

1-[4-Benzyloxycarbamoyl]phenoxymethyl-copoly(styrene-1%-divinylbenzene)-2-bromo-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-indole(9.8 g; 0.59 mmol/g) was suspended in dry THF (150 ml) and dry nitrogenpassed through the solution for one hour. Phenylboronic acid (2.12 g),2M aqueous Na₂CO₃ (10.8 ml) and Pd(PPh₃)₄ (668 mg) were added and thesolution warmed to reflux for 18 h. After this period the resin wasfiltered and washed with DMF (4×25 ml) and DCM (4×25 ml), and thenresuspended in dry THF (150 ml) and treated with fresh reagents for afurther 18 h. The resin was then filtered and washed with DMF (4×25 ml),DCM (4×25 ml), MeOH (4×25 ml) and ether (25 ml). A portion of therecovered resin (100 mg) was then suspended in dry DMF (3.0 ml)containing 5% pyrrolidine and heated to 110° C. for 4 hrs. The resin wasfiltered off and the solvent removed from the filtrate under reducedpressure to afford2-phenyl-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-indole. ¹H (360MHz, CDCl₃) δ1.60-2.10 (6H, br m), 3.21 (2H, t, J=11.0 Hz), 3.46 (2H,m), 3.74 (1H, m), 4.03 (1H, m), 4.61 (1H, t, J=3.0 Hz), 7.11-7.17 (2H,m), 7.25 (2H, m), 7.46 (2H, m), 7.66 (3H, m) and 8.17 (1H, br s).

(f)1-[4-Benzyloxycarbamoyl]phenoxymethyl-copoly(styrene-1%-divinylbenzene)-2-phenyl-1H-indol-3-ylethanol

1-[4-Benzyloxycarbamoyl]phenoxymethyl-copoly(styrene-1%-divinylbenzene)-2-phenyl-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-indole(7.87 g) was suspended in a mixture of DCE (125 ml) and ethanol (12.5ml) containing PPTS (5.83 g) and warmed to 70° C. for 18 h. The resinwas then filtered off and washed with DMF (4×25 ml), DCM (4×25 ml), MeOH(4×25 ml) and ether (25 ml). A portion of the recovered resin (100 mg)was then suspended in dry DMF (3.0 ml) containing 5% pyrrolidine andheated to 110° C. for 4 h. The resin was filtered off and the solventremoved from the filtrate under reduced pressure to afford2-phenyl-1H-indol-3-ylethanol. ¹H (360 MHz, CDCl₃) δ3.21 (2H, t, J=7.0Hz), 3.97 (2H, t, J=7.0 Hz), 7.13-7.22 (2H, m), 7.38 (2H, m), 7.45 (2H,m), 7.62 (3H, m) and 8.12 (1H, br s).

(g) 2-Phenyl-3-[2-(piperidin-1-yl)ethyl]-1H-indole

1-[4-Benzyloxycarbamoyl]phenoxymethyl-copoly(styrene-1%-divinylbenzene)-2-phenyl-1H-indol-3-ylethanol (1.3 g, 0.59 mmol/g)was washed with DCE (5×15 ml) and finally suspended in dry DCE (15 ml).4- Methyl-2,6-di-tert-butylpyridine (1.95 g) was then added and theresulting suspension cooled to −10° C. Trifluoromethanesulphonicanhydride (650 μl) was then added and the reaction stirred at −10° C.for 45 min. The reaction was then warmed to room temperature and theresin washed with DCE (3×15 ml) and resuspended in DCE (15 ml).Piperidine (1.3 g) was then added and the mixture agitated by rotationfor 4 h. The resin was then filtered and washed with DMF (4×25 ml), DCM(4×25 ml), MeOH (4×25 ml) and ether (25 ml). The recovered resin wasthen suspended in dry DMF (20 ml) containing 5% pyrrolidine and heatedto 110° C. for 4 h. The resin was filtered off and the solvent removedfrom the filtrate under reduced pressure to afford2-phenyl-3-[2-(piperidin-1-yl)ethyl]-1H-indole (60 mg). The crudeproduct was purified by flash chromatography (SiO₂; DCM/MeOH/NH₃30:1:0.1) to give the title compound (39 mg). ¹H (500 MHz, CDCl₃) δ1.45(2H, m), 1.63 (4H, m), 2.51 (4H, m), 2.68 (2H, dd, J=10.0 and 1.0 Hz),3.06 (2H, dd, J=10.0 and 1.0 Hz), 7.12 (1H, t, J=5.0 Hz), 7.21 (1H, t,J=5.0 Hz), 7.36 (2H, t, J=3.0 Hz), 7.44 (2H, t, J=3.0 Hz), 7.56 (2H, d,J=3.0 Hz), 7.64 (1H, d, J=1.0 Hz), 8.05 (1H, br s); m/z ES⁺ 305 (M+1)⁺.

Method B:2-Phenyl-3-[2-(4-(2-phenylethyl)piperidin-1-yl)ethyl]-1H-indole Example66

Methanesulphonyl chloride (120 μl) was added to a solution of2-phenyltryptophol (300 mg) and triethylamine (212 μl) in THF (30 ml) at0° C. The reaction mixture was allowed to warm to room temperature over20 minutes and filtered. To the filtrate was added 4-(2-phenylethyl)-piperidine hydrochloride (1.0 g), potassium carbonate (1.0 g), water(1.0 ml) and DMF (20.0 ml) and the mixture warmed to 100° C. for 36hours. The solvent was removed under reduced pressure and the residuepartitioned between water (30 ml) and dichloromethane (50 ml). Theaqueous layer was extracted using dichloromethane (3×50 ml). Thecombined organic layers were dried over sodium sulphate, filtered andevaporated. The residue was purified by column chromatography on silicausing 25% ethyl acetate in hexane as the eluant followed by triturationin hot methanol to give the desired product (216 mg). ¹H nmr (360 MHz,DMSO-d_(G)) 1.10-1.25 (3H, m), 1.44-1.54 (2H, m), 1.64-1.72 (2H, m),1.88-1.98 (2H, m), 2.50-2.64 (4H, m), 2.88-3.02 (4H, m), 6.98-7.03 (1H,m), 7.07-7.20 (4H, m), 7.24-7.29 (2H, m), 7.33-7.40 (2H, m), 7.48-7.54(2H, m), 7.64-7.67 (2H, m), 11.13 (1H, s). Mass Spec. ES⁺: m/z forM+1=409.

In accordance with Method A or Method B as described above, thefollowing compounds were prepared:

Example Structure M wt m/z (M + 1)+ 1

304 305 2

276 277 3

316 317 4

322 323 5

320 321 6

304 305 7

362 363 8

347 348 9

306 307 10

406 407 11

338 339 12

348 349 13

352 353 14

349 350 15

354 355 16

347 348 17

364 365 18

410 411 19

383 384 20

453 454 21

419 420 22

290 291 23

292 293 24

278 279 25

292 293 26

319 320 27

417 418 28

319 320 29

333 334 30

388 389 31

405 406 32

364 365 33

345 346 34

292 293 35

304 305 36

318 319 37

332 333 38

264 265 39

276 277 40

392 393 41

440 441 42

391 392 43

318 319 44

318 319 45

308 309 46

470 471 47

348 349 48

296 297 49

322 323 50

435 436 51

458 459 52

336 337 53

292 293 54

332 333 55

318 319 56

396 397 57

362 363 58

370 371 59

334 335 60

407 408 61

405 406 62

419 420 63

433 434 64

423 424 65

455 456 66

409 410 67

384 385 68

451 452 69

451 452 70

506 507 71

501 502 72

306 307 73

332 333 74

347 348 75

310 311 76

336 337 77

350 351 78

313 314 79

339 340 80

353 354 81

308 309 82

334 335 83

348 349 84

292 293 85

332 333 86

410 411 87

264 265 88

362 363 89

296 297 90

296 297 91

303 304 92

346 347 93

314 315 94

323 324 95

323 324 96

414 415 97

332 333 98

381 382 99

437 438 100

318 319 101

332 333 102

318 319 103

332 333 104

347 348 105

347 348 106

334 335 107

336 337

EXAMPLE 108 5-Bromo-2-phenyl-3-[2-(piperidin-1-yl)ethyl]-1H-indole

1-Phenyl-4-(1-piperidinyl)butan-1-one

γ-Chlorobutyrophenone (25.0 g, 0.14 mol), piperidine (11.65 g, 0.14mol), potassium carbonate (28.3 g, 0.21 mol) and sodium iodide (30.8 g,0.21 mol) were dissolved in isopropyl alcohol (150 ml) and heated underreflux for 20 hours. The solvent was removed in vacuo and the residuepartitioned between ether and water. The organic phase was washed withbrine, dried (sodium sulphate) and evaporated to give a brown oil.Chromatography on silica gel with dichloromethane-methanol-ammonia(98:2:0.2) as the eluent yielded the title compound (9.67 g, 31%) as abrown oil. δ_(H) (250 MHz, CDCl₃) 1.3-1.5 (2H, m, piperidine H-4),1.5-1.6 (4H, m, piperidine H-3), 1.8-2.0 (2H, q, J 7, CH₂CH₂CH₂),2.3-2.5 (6H, m, CH₂), 3.0 (2H, t, J 7, COCH₂), 7.4-7.6 (3H, m, ArH-4 andH-3), 8.0 (2H, d, J 5, ArH-2); m/z (ES⁺) 232 ( M⁺+H).

5-Bromo-2-phenyl-3-[2-(piperidin-1-yl)ethyl]-1H-indole

4-Bromophenylhydrazine hydrochloride (1.45 g, 6.5 mmol) and1-phenyl-4-(1-piperidinyl)butan-1-one (1.50 g, 6.5 mmol) were dissolvedin ethanol (10 ml) and stirred at 25° C. for 4 hours. The solid wasfiltered and washed with ethanol and ether. The white product wasdissolved in trifluoroacetic acid (10 ml) and heated at 70° C. for 2hours. The reaction mixture was basified with saturated potassiumcarbonate solution and extracted into ethyl acetate. The organic phasewas washed with brine, dried (sodium sulphate) and evaporated to give ayellow oil. Chromatography on silica gel withdichloromethane-methanol-ammonia (98:2:0.2) as eluent yielded the titlecompound (0.51 g, 20%) as a white solid. Oxalate salt, white crystals,mp 121-122° C. (from methanol/ether) (Found: C, 58.07; H, 5.23; N, 6.01.C₂₁H₂₃BrN₂. C₂H₂O₄. 0.1H₂O requires C, 58.14; H, 5.35; N, 5.90%); δ_(H)(360 MHz, d_(G)-DMSO) 1.5-1.6 (2H, m, piperidine H-4), 1.7-1.8 (4H, m,piperidine H-3), 3.1-3.3 (8H, m, CH₂), 7.2 (1H, dd, J 2 and 8, indoleH-6), 7.3 (1H, d, J 8, indole H-7), 7.4 (1H, t, J 7, Ar H-4), 7.5 (2H,t, J 7, Ar H-3), 7.6 (2H, d, J 7, Ar H-2), 7.8 (1H, ds, J 2, indoleH-4), 11.6 (1H, br s, indole NH); m/z (ES⁺) 383 ( M⁺+H).

The following Examples were made in the same way as Example 108:

EXAMPLE 109 5-Chloro-2-phenyl-3-[2-(piperidin-1-yl)ethyl]-1H-indole

Trifluoroacetic acid salt, white crystals, mp 153-154° C. (from ethanol)(Found: C, 60.03; H, 5.21; N, 6.15. C₂₁H₂₃CIN₂. C₂HF₃O₂. 0.4H₂O requiresC, 60.04; H, 5.43; N, 6.09%); with the nitrogen protonated, piperidineprotons become non-equivalent. δ_(H) (360 MHz, d_(G)-DMSO) 1.3-1.5 (1H,m, piperidine H-4), 1.6-1.8 (3H, m, piperidine H-4′ and H-3), 1.8-1.9(2H, d, J 7, piperidine H-3′), 2.9-3.1 and 3.2-3.4 (6H, m, CH₂), 3.60(2H, d J 7, piperidine H-2), 7.15 (1H, dd, J 2 and 9, indole H-6), 7.40(1H, d, J 9, indole H-7), 7.45 (2H, t, J 7, Ar H-4), 7.55 (2H, t, J 7,Ar H-3), 7.65 (1H, d, J 7, Ar H-2), 7.75 (1H, s, indole H-4), 11.6 (1H,br s, indole-NH); m/z (ES⁺) 383 (M⁺+H).

EXAMPLE 110 5-Fluoro-2-phenyl-3-[2-(piperidin-1-yl)ethyl]-1H-indole

Trifluoroacetic acid salt, white crystals mp 141-143° C. (from ethanol)(Found: C, 45.38; H, 3.39; N, 3.99. C₂₁H₂₃FN₂. 3.6 CF₃COOH. 0.5 H₂Orequires C, 45.65; H, 3.75; N, 3.78%); with the nitrogen protonated,piperidine methylene protons become non-equivalent. δ_(H) (360 MHz,CDCl₃) 1.3-1.4 (1H, m, piperidine H-4), 1.8-2.0 (5H, m, piperidine H-4′and H-3), 2.60-2.65 (2H, t, J 12, piperidine H-2), 3.15 (2H, m,—CH₂CH₂N), 3.25 (2H, m, —CH₂CH₂N), 3.60 (2H, d, J 12, piperidine H-2′),6.9 (1H, ddd, J 2, 9 and 9, indole H-6), 7.2 (1H, dd, J 2 and 9, indoleH-4), 7.25 (1H, m, indole H-7), 7.4 (1H, m, Ar H-4), 7.4-7.6 (4H, m, ArH-3 and H-4); m/z (ES⁺) 323 (M⁺+H).

EXAMPLE 111 7-Bromo-2-phenyl-3-[2-(piperidin-1-yl)ethyl]-1H-indole

Oxalate salt, white crystals, mp 206-207° C. (from methanol/ether)(Found: C, 56.97; H, 4.95; N, 5.86. C₁₂H₂₃BrN₂. 1.2C₂H₂O₄ requires C,57.20; H, 5.21; N, 5.70%); δ_(H) (360 MHz, d_(G)-DMSO) 1.4-1.6 (2H, m,piperidine H-4), 1.6-1.8 (4H, m, piperidine H-3), 3.0-3.4 (8H, m, CH₂),7.0 (1H, t, J 8, indole H-5), 7.25-7.8 (7H, m, ArH), 11.5 (1H, br s,indole NH): m/z (ES⁺) 383 (M⁺+H).

EXAMPLE 112 7- Chloro-2-phenyl-3-[2-(piperidin-1-yl)ethyl]-1H-indole

Oxalate salt, white crystals, mp 178-179° C. (from methanol/ether)(Found: C, 63.81; H, 5.82; N, 6.47. C₂₁H₂₃ClN₂. 1.1C₂H₂O₄ requires C,63.63; H, 5.80; N, 6.40%); δ_(H) (360 MHz, d_(G)-DMSO) 1.3 (2H, m,piperidine H-4), 1.7-1.9 (4H, m, piperidine H-3), 3.1-3.4 (8H, m, CH₂),7.05 (1H, t, J 8, indole H-5), 7.2 (1H, d, J 8, indole H), 7.45 (1H, t,J 7, Ar H-4), 7.55 (2H, t, J 7, Ar H-3), 7.65 (3H, m, Ar H-2 and indoleH), 11.55 (1H, br s, indole NH); m/z (ES⁺) 339 (M⁺+H).

EXAMPLE 113 5-Methyl-2-phenyl-3-[2-(piperidin-1-yl)ethyl]-1H-indole

Oxalate salt, white powder, mp 163-164° C. (from methanol/ether) (Found:C, 68.30; H, 6.52; N, 6.54. C₂₂H26N₂. 1.25C₂H₂O₄ requires C, 68.28; H,6.67; N, 6.50%); δ_(H) (360 MHz, d_(G)-DMSO) 1.3-1.9 (6H, m, piperidineH-3 and H-4), 2.4 (3H, s, ArCH₃), 2.8-3.6 (8H, m, CH₂), 6.9 (1H, d, J 8,indole H-6), 7.25 (1H, d, J 8, indole H-7), 7.4 (2H, m, indole H-4 andAr H-4), 7.5 (2H, t, J 8, Ar H-3), 7.6 (2H, d, J 8, Ar H-2), 11.2 (1H,br s, indole NH); m/z (ES⁺) 319 (M⁺+H).

EXAMPLE 114 7-Fluoro-2-phenyl-3-[2-(piperidin-1-yl)ethyl]-1H-indole

δ_(H) (500 MHz, CDCl₃) 1.5 (2H, m, piperidine H-4), 1.6-1.9 (4H, m,piperidine H-3), 2.4-2.6 (4H, m, piperidine H-2), 2.8 (2H, m, CH₂CH₂N),3.1 (2H, m, CH₂CH₂N), 6.9 (1H, dd, J 8 and 11, indole H-6), 7.05 (1H, m,indole H-5), 7.4 (2H, m, indole H-4 and Ar H-4), 7.5 (2H, t, J 8, ArH-3), 7.6 (2H, d, J 8, Ar H-2), 8.2 (1H, br s, indole NH); m/z (ES⁺) 323(M⁺+H).

EXAMPLE 115 4-Fluoro-2-phenyl-3-[2-(piperidin-1-yl)ethyl]-1H-indole

δ_(H) (360 MHz, CDCl₃) 1.40-1.45 (2H, m, piperidine H-4), 1.5-1.8 (4H,m, piperidine H-3), 2.4-2.6 (4H, m, piperidine H-2), 2.6-2.8 (2H, m,CH₂CH₂N), 3.1-3.2 (2H, m, CH₂CH₂N), 6.7-6.8 (1H, m, indole H-5), 7.0-7.1(2H, m, indole H-6 and H-7), 7.4 (1H, m, Ar H-4), 7.5 (2H, t, J 7, ArH-3), 7.6 (2H, d, J 7, Ar H-2), 8.2 (1H, br s, indole NH); m/z (ES⁺) 323(M⁺+H).

EXAMPLE 116 4-Chloro-2-phenyl-3-[(2-(piperidin-1-yl)ethyl]-1H-indole

δ_(H) (360 MHz, CDCl₃) 1.4-1.8 (6H, m, piperidine H-4 and H-3), 2.6-2.8(4H, m, piperidine H-2), 2.8-3.0 (2H, m, CH₂CH₂N), 3.25-3.30 (2H, m,CH₂CH₂N), 7.05-7.6 (8H, m, ArH), 8.5 (1H, br s, indole NH); m/z (ES⁺)339 (M⁺+H).

EXAMPLE 117 6-Fluoro-2-phenyl-3-[2-(piperidin-1-yl)ethyl]-1H-indole

Oxalate salt, white crystals, mp 214-215° C. (from methanol/ether)(Found: C, 66.85; H, 6.12; N, 7.11. C₂₁H₂₃FN₂. C₂H₂O₄ requires C, 66.98;H, 6.11; N, 6.79%); δ_(H) (360 MHz, d_(G)-DMSO) 1.45-1.60 (2H, m,piperidine H-4), 1.70-1.80 (4H, m, piperidine H-3), 3.2-3.4 (8H, m,CH₂), 6.9 (1H, dt, J 2 and 10, indole H-5), 7.1 (1H, dd, J 2 and 10,indole H-7), 7.4 (1H, t, J 7, Ar H-4), 7.55 (2H, t, J 7, Ar H-3),7.6-7.7 (3H, m, Ar H-2 and indole H-4), 11.4 (1H, br s, indole NH); m/z(ES⁺) 323 (M⁺+H).

EXAMPLE 118 6-Chloro-2-phenyl-3-[2-(piperidin-1-yl)ethyl]-1H-indole

Oxalate salt, white crystals; ml) >230° C. (from methanol/ether) (FoundC, 64.52; H, 5.96; N, 6.77. C₂₁H₂₃ClN₂. C₂H₂O₄ requires C, 64.41; H,5.88; N, 6.53%), δ_(H) (360 MHz, d₆-DMSO) 1.3-1.4 (2H, m, piperidineH-4), 1.5-1.6 (4H, m, piperidine H-3), 2.8-3.1 (8H, m, CH₂), 6.9 (1H, d,J8, indol H-5), 7.2-7.3 (2H, m, indole H-7 and Ar H-4), 7.3-7.4 (2H, t,J 7, Ar H-3), 7.4-7.5 (3H, m, indole H-4 and Ar H-2), 11.3 (1H, br s,indole NH); m/z (ES⁺) 339 (M⁺+H).

EXAMPLE 119 6-Methyl-2-phenyl-3-[2-(piperidin-1-yl)ethyl]-1-H indole

Oxalate salt, white crystals, mp 112-115° C. (from methanol/ether)(Found: C, 69.07; H, 6.85; N, 6.95. C₂₂H₂₆N₂. C₂H₂O₄. 0.5H₂O requires C,69.04; H, 7.00; N, 6.71%); δ_(H) (360 MHz, DMSO) 1.45-1.60 (2H, m,piperidine H-4), 1.7-1.8 (4H, m, piperidine H-3), 2.4 (3H, s, ArCH₃),3.1-3.4 (8H, m, CH₂), 6.9 (1H, d, J 8, indole H-5), 7.2 (1H, s, indoleH-7), 7.4 (1H, m, Ar H-4), 7.5-7.6 (3H, m, indole H-4+Ar H-3), 7.6 (2H,t, J 7, Ar H-2), 11.2 (1H, br s, indole NH); m/z (ES⁺) 319 (M⁺+H). Thetitle compound was analysed as a mixture with 25 mol % of4-methyl-2-phenyl-3-[2-(piperidinyl)ethyl]-1H-indole.

EXAMPLE 120 4-Bromo-2-phenyl-3-[2-(piperidin-1-yl)ethyl]-1H-indole

Oxalate salt, white crytals, mp >230° C. (from methanol/ether) (Found C,60.62; H, 6.23; N, 6.08: C₂₁H₂₃BrN₂. 0.5C₂H₂O₄. C₂H₅OH requires C,60.76; H, 6.37; N, 5.90%); δ_(H) (360 MHz, d_(G)-DMSO) 1.3-1.4 (2H, m,piperidine H-4), 1.4-1.5 (4H, m, piperidine H-3), 2.6-2.7 (4H, m,piperidine H-2), 2.8 (2H, m, CH₂CH₂N), 3.1 (2H, m, piperidine H-2), 2.8(2H, m, CH₂CH₂N), 3.1 (2H, m, CH₂CH₂N), 6.9 (1H, t, H 8, indole H-6),7.1 (1H, d, J 8, indole H), 7.2 (1H, d, J 8, indole H), 7.3 (1H, t, J 7,Ar H-4), 7.4 (2H, t, J 7, Ar H-3), 7.5 (2H, d, J 7, Ar H-2), 11.5 (1H,br s, indole NH); m/z (ES⁺) 383 (M⁺+H).

EXAMPLE 121 6-Bromo-2-phenyl-3-[2-(piperidin-1-yl)ethyl]-1H-indole

Oxalate salt, white crystals, mp >230° C. (from methanol/ether) (Found:C, 55.16; H, 5.02; N, 5.73. C₂₁H₂₃BrN₂. 1.4C₂H₂O₄. 1.4H₂O requires C,55.40; H, 5.08; N, 5.43%); δ_(H) (360 MHz, d_(G)-DMSO) 1.60-1.65 (2H, m,piperidine H-4), 1.8-1.9 (4H, m, piperidine H-3), 3.2-3.4 (8H, m, CH₂),7.3 (1H, dd, J 3 and 8, indole H-5), 7.5 (1H, t, J 7, Ar H-4), 7.6-7.7(3H, m, indole H-7 and Ar H-3), 7.7-7.8 (3H, m, indole H-4 and Ar H-2),11.6 (1H, br s, indole NH), m/z (ES⁺) 383 (M⁺+H).

EXAMPLE 122 7- Methyl-2-phenyl-3-[2-(piperidin-1-yl)ethyl]-1H-indole

Oxalate salt, white crystals, mp 159-161° C. (from methanol/ether)(Found: C, 68.89; H, 6.81; N, 6.78. C₂₂H₂₆N₂. C₂H₂O₄. 0.6H₂O requires68.75, H, 7.02; N, 6.68%); δ_(H) (360 MHz, d_(G)-DMSO) 1.8-1.9 (2H, m,piperidine H-4), 2.0-2.1 (4H, m, piperidine H-3), 2.8 (3H, s, ArCH₃),3.4-3.6 (8H, m, CH₂), 7.2 (2H, m, indole-H ), 7.7-8.0 (6H, m, ArH), 11.4(1H, s, indole NH); m/z (ES⁺) 319 (M⁺+H).

EXAMPLE 123 5,7-Difluoro-2-phenyl-3-[2-(piperidin-1-yl)ethyl]-1H-indole

Oxalate salt, white crystals, mp 185-187° C. (from methanol/ether)(Found: C, 59.53; H, 5.42; N, 5.31. C₂₁H₂₂F₂N₂. 1.5C₂H₂O₄. 0.2C₂H₅OH.0.5H₂O requires C, 59.36; H, 5.55; N, 5.67%); δ_(H) (360 MHz,d_(G)-DMSO) 1.4-1.8 (6H, m, piperidine H-4 and H-3), 3.2-3.4 (8H, m,CH₂), 7.0 (1H, dt, J 2 and 10), 7.4 (1H, dd, J 2 and 10), 7.45 (1H, t, J7, Ar H-4), 7.55 (2H, t, J 7, Ar H-3), 7.7 (2H, d, J 7, Ar H-2), 11.8(1H, s, indole NH); m/z (ES⁺) 341 (M⁺+H).

EXAMPLE 124 2,6-Diphenyl-3-[2-(piperidin-1-yl)ethyl]-1H-indole

Oxalate salt, white crystals, mp 129-131° C. (from methanol/ether)(Found: C, 72.50; H, 6.26; N, 6.00. C₂₇H₂₈N₂. C₂H₂O₄. 0.5H₂O requires C,72.63; H, 6.52; N, 5.84%); δ_(H) (360 MHz, dr-DMSO) 1.5-1.6 (2H, m,piperidine H-4), 1.7-1.8 (4H, m, piperidine H-3), 3.1-3.4 (8H, m, CH₂),7.2-7.8 (13H, m, Ar-H ), 11.4 (1H, br s, indole NH); m/z (ES⁺) 381(M⁺+H).

EXAMPLE 125 2,4-Diphenyl-3-[2-(piperidin-1-yl)ethyl-1H-indole

Oxalate salt, white crystals, mp 142-143° C. (from methanol/ether)(Found: C, 70.81; H, 6.18; N, 5.73. C₂₇H₂₈N₂. 1.25C₂H₂O₄. 0.4H₂Orequires C, 70.82; H, 6.31; N, 5.60%); δ_(H) (360 MHz, d_(G)-DMSO)1.3-1.4 (2H, m, piperidine H-4), 1.4-1.5 (4H, m, piperidine H-3),2.3-2.6 (6H, m, CH₂), 2.9 (2H, m, CH₂CH₂N), 6.85 (1H, d, J 7, indole H),7.2 (1H, t, J 7, indole H-6), 7.4-7.7 (11H, m, ArH), 11.6 (1H, s, indoleNH); m/z (ES⁺) 381 (M⁺+H).

EXAMPLE 126 4- Methoxy-2-phenyl-3-[2-(piperidin-1-yl)ethyl]-1H-indole

Off-white solid, mp 260-262° C.; δ_(H) (360 MHz, d_(G)-DMSO) 1.74 (6H,m, 3×CH₂), 2.90 (2H, m, NCH₂), 3.30 (4H, m, 2×NCH₂), 3.50 (2H, m,ArCH₂), 3.91 (3H, s, OCH₃), 6.53 (1H, d, J 8, CH), 7.02 (1H, d, J 8,CH), 7.11 (1H, dd, J 8 and 8, CH), 7.41 (1H, dd, J 8 and 8, CH), 7.52(2H, dd, J 8 and 8, 2×CH) and 7.59 (2H, d, J 8, 2×CH); m/z (ES⁺) 335(M⁺+H).

EXAMPLE 127 7- Methoxy-2-phenyl-3-[2-(piperidin-1-yl)ethyl]-1H-indole

Oxalate salt, white solid, mp 203-205° C. (Found: C, 66.2; H, 6.0; N,7.2; C₂₄H₂₈N₂O₅ requires C, 67.9; H, 6.6; N, 6.6%); δ_(H) (360 MHz,d_(G)-DMSO) 1.56 (2H, m, CH₂), 1.72 (4H, m, 2×NCH₂CH₂), 3.18 (8H, m,3×NCH₂ and ArCHO, 3.92 (3H, s, OCH₃), 6.71 (1H, d, J8, CH), 6.99 (1H,dd, J 8 and 8, CH), 7.23 (1H, d, J 8, CH), 7.39 (1H, dd, J 8 and 8, CH),7.50 (2H, dd, J 8 and 8, 2×CH) and 7.63 (2H, d, J 8, 2×CH); m/z (ES⁺)335 (M⁺+H).

EXAMPLE 128 2-Phenyl-3-[2-(piperidin-1-yl)prop-1-yl]-1H-indole

a) 3-[2-(Piperidin-1-yl)prop-1-yl]-1H-indole

To a solution of indole-3-acetone (5.0 g, 29 mmol) in anhydrous1,2-dichloroethane (100 ml) under an atmosphere of nitrogen was addedpiperidine (2.9 ml, 29 mmol), and glacial acetic acid (1.66 ml, 29 mmol)followed by sodium triacetoxyborohydride (6.8 g, 32 mmol). On completeaddition the reaction mixture was stirred at room temperature for 17hours. The mixture was basified by the addition of a saturated solutionof sodium hydrogen carbonate, the layers were separated and the organiclayer dried over anhydrous magnesium sulfate, filtered and evaporated invacuo. The residue was purified by column chromatography on silicaelution with 5% CH₃OH in CH₂Cl₂+0.5% 0.88 ammonia to give the titleproduct (3 g, 43%); δ_(H) (360 MHz; CDCl₃) 0.99 (3H, d, J 6.5 Hz, —CH₃),1.43-1.51 (2H, m, aliphatics), 1.60-1.69 (4H, m, aliphatics), 2.56-2.70(5H, m, aliphatics+indole CH_(A)CH_(B)), 2.87-2.99 (1H, m, indoleCH_(A)H_(B)CH (piperidine)), 3.12 (1H, dd, J 13.9 and 3.6 Hz, indoleCH_(A)CH_(B)), 7.02 (1H, d, J 1.9 Hz, indole H2), 7.09 (1H, m, indoleH6), 7.17 (1H, m, indole H5), 7.34 (1H, d, J 8.0 Hz, indole H7), 7.61(1H, d, J 7.6 Hz, indole H4), 8.01 (1H, bs, indole NH); m/z (ES⁺) 243(M⁺+H, 100%).

b) 1-tert-Butoxycarbonyl-3-[2-(piperidin-1-yl)prop-1-yl]-1H-indole

To a solution of 3-[2-(piperidin-1-yl)prop-1-yl]-1H-indole (3.0 g, 12.4mmol) in anhydrous dichloromethane under an atmosphere of nitrogen wasadded di-tert-butyl dicarbonate (3.0 g, 13.6 mmol) followed by4-dimethylaminopyridine (1.66 g, 13.6 mmol). On complete addition thereaction mixture was stirred at room temperature for 3 hours thenevaporated in vacuo. The residue was purified by column chromatographyon silica eluting with 2% CH₃OH in CH₂Cl₂+0.5% 0.88 ammonia to give thetitle compound (3.6 g, 85%); δ_(H) (360 MHz; CDCl₃) 1.00 (3H, d, J 6.5Hz, —CH₃), 1.43-1.52 (2H, m, aliphatics), 1.59-1.65 (4H, m, aliphatics),1.67 (9H, S, O₂C(CH₃)₃), 2.54 (1H, dd, J 13.9 and 9.4 Hz, indoleCH_(A)H_(B)), 2.59-2.65 (4H, m, aliphatics), 2.88-2.97 (1H, m, indoleCH_(A)H_(B)CH), 3.01 (1H, dd, J 13.9 and 3.7 Hz, indole CH_(A)H_(B)),7.19-7.34 (2H, m, indole H5+H6), 7.43 (1H, s, indole H2), 7.53 (1H, d,J=7.7 Hz, indole H4), 8.10 (1H, broad doublet, indole H7); m/z (ES⁺) 343(M⁺+H, 100%).

c)2-Bromo-1-tert-butoxycarbonyl-3-[2-(piperidin-1-yl)prop-1-yl]-1H-indole

To a solution of 2,2,6,6-tetramethylpiperidine (5.3 ml, 31.6 mmol) inanhydrous tetrahydrofuran (50 ml) cooled to −78° C. under an atmosphereof nitrogen was added in a dropwise manner n-butyllithium (12.6 ml of a2.5M solution in hexanes, 31.6mmol). On complete addition the reactionmixture was allowed to warm to 0° C. and stirred at this temperature for5 minutes. Re-cooled to −78° C. and a solution of the1-tert-butoxycarbonyl-3-[2-(piperidin-1-yl)prop-1-yl]-1H-indole inanhydrous tetrahydrofuran (50 ml) added via a cannula at such a ratethat the temperature did not rise above −50° C. On complete addition thereaction mixture was stirred at −78° C. for 4 hours then1,2-dibromotetrafluoroethane (3.78 ml, 31.6 mmol) added; the reactionmixture was allowed to warm to room temperature and stirred for 18hours. The solvent was removed in vacuo and the residue purified bycolumn chromatography on silica eluting with 2% CH₃OH in CH₂Cl₂+0.5%0.88 ammonia to give the title compound (1.5 g, 34%); δ^(H) (³⁶⁰ MHz;CDCl₃) 1.32 (3H, d, J 6.7 Hz, CH₃), 1.71 (9H, s, O₂C(CH₃)₃), 2.99-3.05(1H, m, indole CH_(A)H_(B)), 3.55-3.67 (1H, m, indole CH_(A)H_(B)CH),3.74 (1H, d, J 13.2 Hz, indole CH_(A)H_(B)), 7.26-7.33 (2H, m, indoleH5+H6), 7.92 (1H, dd, J 6.6 and 3.7 Hz, indole H4), 8.05 (1H, d, J 5.8and 2.2 Hz, indole H7), piperidine protons very broad and merged intobaseline; m/z (ES⁺) 421/423 (M⁺+H, 100%).

d) 2-Phenyl-3-[2-(piperidin-1-yl)prop-1-yl]-1H-indole

To a solution of the2-bromo-1-tert-butoxycarbonyl-3-[2-(piperidin-1-yl)prop-1-yl]-1H-indole(750 mg, 1.8 mmol) and phenyl boronic acid (326 mg, 2.6 mmol) in amixture of ethanol (25 ml) and toluene (25 ml) was added sodiumcarbonate (4.4 ml of a 1.0M solution in water, 4.4 mmol), lithiumchloride (227 mg, 5.3 mmol), andtetrakis(triphenylphosphine)-palladium(0) (100 mg, 0.08 mmol)sequentially. The reaction mixture was heated to reflux under anatmosphere of nitrogen for 65 hours. The reaction was cooled andevaporated in vacuo; the residue was azeotroped with toluene (2×50 ml).The residue was dissolved in anhydrous dichloromethane (50 ml) andtrifluoroacetic acid (5 ml, 65 mmol) added and the mixture stirred atroom temperature for 19 hours. The reaction mixture was basified by theaddition of a saturated solution of sodium hydrogen carbonate, theorganic layer was separated and dried over anhydrous magnesium sulfate,filtered and evaporated in vacuo. The product was purified bypreparative TLC eluting with 5% CH₃OH in CH₂Cl₂+0.5% 0.88 ammonia andthe oxalate salt formed from EtOH/Et2O to give the title compound (71mg, 10%); mp 240° C.; (Found: C, 71.58; H, 7.01; N, 7.01. C₂₂H₂₆N₂.0.9(CO₂H)₂ requires C, 71.58; H, 7.00; N, 7.03%); δ^(H) (360 MHz;d_(G)-DMSO) 0.96 (3H, d, J 6.5 Hz, —CH₃), 1.44-1.64 (2H, m, aliphatics),1.70-1.88 (4H, m, aliphatics), 3.04-3.30 (5H, m, aliphatics), 3.38-3.52(2H, m, indole CH_(A)H_(B)+indole CH_(A)H_(B)CH), 7.04 (1H, t, J 7.7 and7.1 Hz, indole H5), 7.13 (1H, t, J 7.7 and 7.3 Hz, indole H6), 7.38 (1H,d, J 8.0 Hz, indole H4), 7.42 (1H, d, J 7.3 Hz, indole H7), 7.53 (2H, t,J 7.8 and 7.5 Hz, aromatics), 7.65-7.69 (3H, m, aromatics), 11.34 (1H,s, indole NH); m/z (ES⁺) 319 (M⁺+H, 100%).

EXAMPLES 129 TO 231 Method C:2-[3,5-Bis(trifluoromethyl)phenyl]-3-[2-(N-methyl-N-isopropylamino)ethyl]-1H-indole(Example 129)

(a)1-tert-Butoxycarbonyl-2-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-indole

To a degassed solution of1-tert-butoxycarbonyl-2-bromo-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-indole(2.0 g), 3,5-bis(trifluoromethyl)phenylboronic acid (2.43 g) and Na₂CO₃(aq., 2N, 8.8 ml) in tetrahydrofuran was addedtetrakis(triphenylphosphine)-palladium(0) (0.55 g). The resultingsolution was then warmed to reflux for 18 h, cooled to room temperatureand partitioned between ethyl acetate and water. The organic layer wasseparated, washed with water and brine, dried over MgSO₄, filtered andthe solvent removed under reduced pressure. The residue was purified byflash chromatography (SiO₂; 3-5% ethyl acetate/hexanes) to afford thetitle compound (2.1 g). ¹H NMR (CDCl₃) δ1.23 (s, 9H), 1.45-1.71 (br m,6H), 2.82 (t, 2H, J=7.2 Hz), 3.37 (m, 1H), 3.61 (m, 2H), 3.98 (m, 1H),4.50 (t, 1H, J=3.5 Hz), 7.30 (t, 1H, J=7.0 Hz), 7.41 (t, 1H, J=7.0 Hz),7.60 (d, 1H, J=10.0 Hz), 7.89 (s, 1H), 7.91 (s, 2H), 8.27 (d, 1H, J=10.0Hz).

(b)1-tert-Butoxycarbonyl-2-[3,5-bis(trifluoromethyl)phenyl]-3-(2-hydroxyethyl)-1H-indole

PPTS (95 mg) was added to a stirred solution of1-tert-butoxycarbonyl-2-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-indole(2.1 g) in ethanol (50 ml) and warmed to 50° C. for 3 h. The reactionmixture was allowed to cool to room temperature, poured into brine (80ml) and extracted into diethyl ether. The organic layers were separated,dried over MgSO₄, filtered and the solvent removed under reducedpressure to give a clear oil which crystallized on standing (1.67 g). ¹HNMR (CDCl₃) δ1.23 (s, 9H), 2.79 (t, 2H, J=7.2 Hz), 3.86 (m, 2H), 7.27(t, 1H, J=7.0 Hz), 7.34 (t, 1H, J=7.0 Hz), 7.60 (d, 1H, J=10.0 Hz), 7.90(s, 3H), 8.28 (d, 1H, J=10.0 Hz).

(c)2-[3,5-Bis(trifluoromethyl)phenyl]-3-[2-(N-methyl-N-isopropylamino)ethyl]-1H-indole

Trifluoromethanesulphonic anhydride (10 ml) was added to a cooled (−78°C.) solution of1-tert-butoxycarbonyl-2-[3,5-bis(trifluoromethyl)-phenyl]-3-(2-hydroxyethyl)-1H-indole(20 mg) in dry dichloromethane (1.0 ml). After 30 minN-methylisopropylamine (100 ml of a 1.0 mmol solution indichloromethane) was added. The reaction was allowed to warm to roomtemperature overnight and was then treated with methylisocyanatepolystyrene resin (100 mg @ 1.0 mmol/g). The reaction solution wasfiltered and the solvent removed under reduced pressure. The residue wastaken up in 0.2N NaO Me/methanol (1.0 ml) and warmed to 45° C. for twohours. The solvent was removed under reduced pressure and the titlecompound recovered by ion exchange chromatography (SCX, 2N NH₃/MeOH),m/z (m+H)⁺429.

In accordance with Method C as described above, the following compoundswere prepared:

Example Structure mol weight m/z (M + 1) + 129

428.42 429 130

484.53 486 131

496.54 498 132

442.45 443 133

454.46 455 134

428.42 429 135

456.48 457 136

454.46 455 137

455.45 456 138

484.53 486 139

442.41 443 140

426.41 427 141

469.48 470 142

512.55 514 143

568.65 570 144

499.50 501 145

554.58 556 146

530.56 532 147

428.42 429 148

456.48 457 149

440.44 441 150

454.46 455 151

468.49 469 152

468.49 469 153

468.49 469 154

454.46 455 155

545.53 547 156

470.46 471 157

468.49 469 158

468.49 469 159

482.52 484 160

454.46 455 161

482.52 484 162

470.46 471 163

508.56 510 164

454.46 455 165

488.48 489 166

470.46 471 167

546.56 548 168

400.37 401 169

483.50 485 170

518.51 520 171

454.34 455 172

418.36 419 173

414.40 415 174

428.42 429 175

412.38 413 176

310.42 311 177

366.53 368 178

324.45 325 179

350.48 351 180

324.45 325 181

322.43 323 182

340.47 341 183

394.58 396 184

310.42 311 185

338.47 339 186

336.46 337 187

337.44 338 188

366.53 368 189

324.40 325 190

308.40 309 191

405.56 407 192

422.59 424 193

427.57 429 194

450.65 452 195

391.54 393 196

381.50 382 197

427.57 429 198

363.48 364 199

365.50 366 200

436.58 438 201

412.56 414 202

310.42 311 203

338.47 339 204

322.43 323 205

336.46 337 206

350.48 351 207

391.54 393 208

398.53 400 209

350.48 351 210

336.46 337 211

350.48 351 212

350.48 351 213

364.51 366 214

336.46 337 215

364.51 366 216

352.46 353 217

390.55 392 218

336.46 337 219

392.56 394 220

370.47 371 221

352.46 353 222

282.36 283 223

367.47 368 224

381.50 382 225

381.54 383 226

400.50 402 227

336.34 337 228

314.38 315 229

296.39 297 230

310.42 311 231

294.38 295

What is claimed is:
 1. A compound having formula I, or apharmaceutically acceptable salt thereof;

wherein A represents hydrogen, halogen, cyano, nitro, trifluoromethyl,trifluoromethoxy, C₁₋₆ alkyl or C₁₋₆ alkoxy; B representstrifluoromethyl or trifluoromethoxy,: X and Y independently representhydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy or phenyl; R¹ representshydrogen or C₁₋₆ alkyl; R² represents hydrogen, methyl, ethyl,2-methoxyethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, tert-butylor n-pentyl; and R³ represents C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₉cycloalkyl, aryl, C₃₋₇ heterocycloalkyl, C₃₋₇heterocycloalkyl(C₁₋₆)alkyl, heteroaryl or heteroaryl(C₁₋₆)alkyl, any ofwhich groups may be optionally substituted by one or more substituents;or R² and R³ taken together with the intervening nitrogen atom representa group of formula (a), (b), (c), (d), (e), (f), (g), (h), (i), (j),(k), (l) or (m):

in which the broken line represents an optional chemical bond; Zrepresents oxygen, sulphur, N—R⁶ or CR⁷R⁸; R⁴ represents hydrogen, C₁₋₆alkyl, C₁₋₆ alkoxy(C₁₋₆)alkyl, C₃₋₇ heterocycloalkyl(C₁₋₆)alkyl oraryloxy; R⁵ represents hydrogen, C₁₋₆ alkyl or C₁₋₆ alkoxy(C₁₋₆)alkyl;R⁶ represents hydrogen, —COR⁹ or —CO₂R⁹; or C₁₋₆ alkyl, C₂₋₆ alkenyl,C₃₋₉ cycloalkyl, aryl(C₁₋₆)alkyl, aryl(C₂₋₆)alkenyl, C₃₋₇heterocycloalkyl(C₁₋₆)alkyl or heteroaryl, any of which groups may beoptionally substituted by one or more substituents; R⁷ representshydrogen, hydrocarbon, a heterocyclic group, —COR⁹ or —CO₂R⁹, R⁸represents hydrogen, phenyl or acetoxy; and R⁹ represents C₁₋₆ alkyl. 2.A compound of formula IA, or a pharmaceutically acceptable salt thereof:

wherein R² and R³ are as defined in claim
 1. 3. A compound havingformula I, or a pharmaceutically acceptable salt thereof:

wherein A and B independently represent hydrogen, halogen, cyano, nitro,trifluoromethyl, trifluoromethoxy, C₁₋₆ alkyl or C₁₋₆ alkoxy; Xrepresents hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy or phenyl; Yrepresents phenyl; R¹ represents hydrogen or C₁₋₆ alkyl; R² representshydrogen, methyl, ethyl, 2-methoxyethyl, n-propyl, isopropyl, n-butyl,2-methylpropyl, tert-butyl or n-pentyl; and R³ represents C₁₋₆ alkyl,C₂₋₆ alkenyl, C₃₋₉ cycloalkyl, aryl, C₃₋₇ heterocycloalkyl, C₃₋₇heterocycloalkyl(C₁₋₆)alkyl, heteroaryl or heteroaryl(C₁₋₆)alkyl, any ofwhich groups may be optionally substituted by one or more substituents;or R² and R³ taken together with the intervening nitrogen atom representa group of formula (a), (b), (c), (d), (e), (f), (g), (h), (i), (j),(k), (l) or (m):

in which the broken line represents an optional chemical bond; Zrepresents oxygen, sulphur, N—R⁶ or CR⁷R⁸; R⁴ represents hydrogen, C₁₋₆alkyl, C₁₋₆ alkoxy(C₁₋₆)alkyl, C₃₋₇ heterocycloalkyl(C₁₋₆)alkyl oraryloxy; R⁵ represents hydrogen, C₁₋₆ alkyl or C₁₋₆ alkoxy(C₁₋₆)alkyl;R⁶ represents hydrogen, —COR⁹ or —CO₂R⁹; or C₁₋₆ alkyl, C₂₋₆ alkenyl,C₃₋₉ cycloalkyl, aryl(C₁₋₆)alkyl, aryl(C₂₋₆)alkenyl, C₃₋₇heterocycloalkyl(C₁₋₆)alkyl or heteroaryl, any of which groups may beoptionally substituted by one or more substituents; R⁷ representshydrogen, hydrocarbon, a heterocyclic group, —COR⁹ or —CO₂R⁹; R⁸represents hydrogen, phenyl or acetoxy; and R⁹ represents C₁₋₆ alkyl. 4.A pharmaceutical composition comprising a therapeutically effectiveamount of a compound as claimed in claim 1 in association with apharmaceutically acceptable carrier.
 5. A pharmaceutical compositioncomprising a therapeutically effective amount of a compound as claimedin claim 2 in association with a pharmaceutically acceptable carrier. 6.A pharmaceutical composition comprising a therapeutically effectiveamount of a compound as claimed in claim 3 in association with apharmaceutically acceptable carrier.
 7. A pharmaceutical compositioncomprising a therapeutically effective amount of a compound havingformula I, or a pharmaceutically acceptable salt thereof, in associationwith a pharmaceutically acceptable carrier, further comprising a secondanti-schizophrenic medicament, or a pharmaceutically acceptable saltthereof:

wherein A and B independently represent hydrogen, halogen, cyano, nitro,trifluoromethyl, trifluoromethoxy, C₁₋₆ alkyl or C₁₋₆ alkoxy; X and Yindependently represent hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy orphenyl; R¹ represents hydrogen or C₁₋ ₆ alkyl; R² represents hydrogen,methyl, ethyl, 2-methoxyethyl, n-propyl, isopropyl, n-butyl,2-methylpropyl, tert-butyl or n-pentyl; and R³ represents C₁₋₆ alkyl,C₂₋₆ alkenyl, C₃₋₉ cycloalkyl, aryl, C₃₋₇ heterocycloalkyl, C₃₋₇heterocycloalkyl(C₁₋₆)alkyl, heteroaryl or heteroaryl(C₁₋₆)alkyl, any ofwhich groups may be optionally substituted by one or more substituents,with the proviso that the heterocycloalkyl(C₁₋₆)alkyl andheteroaryl(C₁₋₆)alkyl groups do not include the heterocycle andheteroaryl groups selected from pyridine N-oxide, pyridine,2-hydroxypyridine, indole, benzimidazole, quinoline, pyrimidine,imidazole, naphthyridine, and tetrahydronaphthyridine; or R² and R³taken together with the intervening nitrogen atom represent a group offormula (a), (b), (c), (d), (e), (f), (g), (h), (i), G), (k), (l) or(m):

in which the broken line represents an optional chemical bond; Zrepresents oxygen, sulphur, N—R⁶ or CR⁷R⁸; R₄ represents hydrogen, C₁₋₆alkyl, C₁₋₆ alkoxy(C₁₋₆)alkyl, C₃₋₇ heterocycloalkyl(C₁₋₆)alkyl oraryloxy, R⁵ represents hydrogen, C₁₋₆ alkyl or C₁₋₆ alkoxy(C₁₋₆)alkyl;R⁶ represents hydrogen, —COR⁹ or —CO₂R⁹; or C₁₋₆ alkyl, C₂₋₆ alkenyl,C₃₋₉ cycloalkyl, aryl(C₁₋₆)alkyl, aryl(C₂₋₆)alkenyl, C₃₋₇heterocycloalkyl](C₁₋₆)alkyl or heteroaryl, any of which groups may beoptionally substituted by one or more substituents; R⁷ representshydrogen, hydrocarbon, a heterocyclic group, —COR⁹ or —CO₂R⁹; R⁸represents hydrogen, phenyl or acetoxy; and R⁹ represents C₁₋₆ alkyl;with the proviso that: (i) when A and B independently representhydrogen, halogen, cyano, nitro, alkyl or alkoxy, and X and Yindependently represent hydrogen, halogen, alkyl or alkoxy, then R³ doesnot represent alkyl, and R² and R³ taken together with the interveningnitrogen atom do not represent piperidin-1-yl or morpholin-4-yl; and(ii) when A, B, X, Y and R¹ each represents hydrogen, then R² and R³taken together with the intervening nitrogen atom do not representpiperidin-1-yl, morpholin-4-yl, pyrrolidin-1-yl, 2-methylpiperidin-1-ylor homopiperidin-1-yl.
 8. A pharmaceutical composition as claimed inclaim 4, further comprising a second anti-schizophrenic medicament.
 9. Acomposition as claimed in claim 5 further comprising a secondanti-schizophrenic medicament.
 10. A composition as claimed in claim 6further comprising a second anti-schizophrenic medicament.
 11. A methodfor the treatment of clinical conditions for which a selectiveantagonist of 5-HT_(2A) receptors is indicated which comprisesadministering to a patient in need of such treatment an effective amountof a compound having formula I, or a pharmaceutically acceptable saltthereof:

wherein A and B independently represent hydrogen, halogen, cyano, nitro,trifluoromethyl, trifluoromethoxy, C₁₋₆ alkyl or C₁₋₆ alkoxy; X and Yindependently represent hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy orphenyl; R¹ represents hydrogen or C₁₋₆ alkyl; R² represents hydrogen,methyl, ethyl, 2-methoxyethyl, n-propyl, isopropyl, n-butyl,2-methylpropyl, tert-butyl or n-pentyl; and R³ represents C₁₋₆ alkyl,C₂₋₆ alkenyl, C₃₋₉ cycloalkyl, aryl, C₃₋₇ heterocycloalkyl, C₃₋₇heterocycloalkyl(C₁₋₆)alkyl, heteroaryl or heteroaryl(C₁₋₆)alkyl, any ofwhich groups may be optionally substituted by one or more substituents,with the proviso that the heterocycloalkyl(C₁₋₆)alkyl andheteroaryl(C₁₋₆)alkyl groups do not include the heterocycle andheteroaryl groups selected from pyridine N-oxide, pyridine,2-hydroxypyridine, indole, benzimidazole, quinoline, pyrimidine,imidazole, naphthyridine, and tetrahydronaphthyridine; or R² and R³taken together with the intervening nitrogen atom represent a group offormula (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l) or(m):

in which the broken line represents an optional chemical bond; Zrepresents oxygen, sulphur, N—R⁶ or CR⁷R⁸; R⁴ represents hydrogen, C₁₋₆alkyl, C¹⁻⁶ alkoxy(C¹⁻⁶)alkyl, C₃₋₇ heterocycloalkyl(C₁₋₆)alkyl oraryloxy; R⁵ represents hydrogen, C₁₋₆ alkyl or C₁₋₆ alkoxy(C₁₋₆)alkyl;R⁶ represents hydrogen, —COR⁹ or —CO₂R⁹; or C₁₋₆ alkyl, C₂₋₆ alkenyl,C₃₋₉ cycloalkyl, aryl(C₁₋₆)alkyl, aryl(C₂₋₆)alkenyl, C₃₋₇heterocycloalkyl(C₁₋₆)alkyl or heteroaryl, any of which groups may beoptionally substituted by one or more substituents; R⁷ representshydrogen, hydrocarbon, a heterocyclic group, —COR⁹ or —CO₂R⁹; R⁸represents hydrogen, phenyl or acetoxy; and R⁹ represents C₁₋₆ alkyl;with the proviso that: (i) when A and B independently representhydrogen, halogen, cyano, nitro, alkyl or alkoxy, and X and Yindependently represent hydrogen, halogen, alkyl or alkoxy, than R³ doesnot represent alkyl, and R² and R³ taken together with the interveningnitrogen atom do not represent piperidin-1-yl or morpholin-4yl; and (ii)when A, B, X, Y and R¹ each represents hydrogen, then R² and R³ takentogether with the intervening nitrogen atom do not representpiperidin-1-yl, morpholin-4-yl, pyrrolidin-1-yl, 2-methylpiperidin-1-ylor homopiperidin-1-yl.
 12. A method for the treatment of clinicalconditions for which a selective antagonist of 5-HT_(2A) receptors isindicated, which comprises administering to a patient in need of suchtreatment an effective amount of a compound as claimed in claim
 1. 13. Amethod for the treatment of clinical conditions for which a selectiveantagonist of ⁵-HT_(2A) receptors is indicated, which comprisesadministering to a patient in need of such treatment an effective amountof a compound as claimed in claim
 2. 14. A method for the treatment ofclinical conditions for which a selective antagonist of ⁵-HT_(2A)receptors is indicated, which comprises administering to a patient inneed of such treatment an effective amount of a compound as claimed inclaim 3.